The oncogenic transcription factor c-Myc has a pleiotropic role in a wide range of cell processes and is deregulated in some 70% of human cancers. However, targeting the c-Myc protein directly has proven to be difficult due to a lack of well-defined pockets amenable to small molecule binding. An alternative approach for suppressing c-Myc levels in the cell is through stabilization of the G-quadruplex DNA formation (G4) present in the promoter of the c-MYC gene. Expression of the proto-oncogene c-MYC is regulated by a 27 base pair (Pu27) sequence found in the nuclease hypersensitive element III(1) region (NHEIII1) of the c-MYC gene known to form a G4. Formation of the quadruplex in this sequence is believed to result in a “kink” in the DNA that prevents the polymerase from continuing along its reading frame, ultimately resulting in downregulation of the c-MYC gene.
The use of small molecules to stabilize the G4 conformation and consequently decrease c-MYC expression is an attractive therapeutic goal in cancers where c-Myc is overexpressed. Unfortunately, although some quadruplex stabilizing small molecules have been shown to reduce c-Myc expression in cells, these agents may not be selective and activity cannot always be attributed to a c-MYC quadruplex-dependent mechanism of action. New classes of potent, selective quadruplex stabilizing agents that are active in tissue culture models would be of substantial utility as reagents to study c-Myc biology as well as potential therapeutics.